High-throughput efforts by us and others have provided strong evidence that, in sharp contrast to earlier understanding, much of the mammalian genome is transcribed into noncoding RNA. We now seek to understand if noncoding RNA regulatory networks may relate to the 2-amyloid hypothesis in Alzheimer's disease (AD). This application focuses on a noncoding RNA network that appears to regulate the expression of -secretase-1 (BACE1), a critical enzyme in AD pathophysiology and a prime AD drug target. We have recently reported that a BACE1 noncoding antisense transcript (BACE1-AS) concordantly and potently regulates BACE1 mRNA and protein expression. Important, BACE1-AS concentrations were markedly elevated in human AD patients as well as in amyloid precursor protein transgenic mice, an AD animal model. BACE1-AS is enriched in the cell nucleus but upon exposure to amyloid- 1-42 (A 1-42), or other cellular stressors, this noncoding transcript translocates into the cytoplasm resulting in increased BACE1 mRNA stability, as well as masking of a microRNA binding site on BACE1 mRNA; these appear to be synergistic mechanisms leading to generation of additional A 1-42 in a vicious cycle. This putative feed-forward pathway, linked to the release of BACE1-AS from a nuclear reservoir, may be driving aspects of AD related pathologies. Considering these findings, the present research application focuses on three aims. Our first aim is to gain a detailed mechanistic understanding of the in vitro regulatory effect that BACE1-AS exerts on BACE1 expression as well as the potential impact of BACE1-AS on AD related pathologies. Second, we will seek to verify that the in vitro regulatory effects of BACE1-AS on BACE1 expression are also present in vivo in mouse brain. Here we will develop BACE1-AS transgenic mice to determine if the overexpression of this noncoding RNA is sufficient to cause or accelerate AD- like pathology. Third, we will address the issue as to whether BACE1-related transcripts, notably BACE1-AS, may be useful as biomarkers for studies on AD. To complement our studies on AD and control brain samples, we shall investigate, in a large number of peripheral blood mononuclear cell samples, whether peripheral BACE1-related biomarkers might be useful as biomarkers. Overall, these experiments promise to yield significant insights into mechanisms by which BACE1 expression is controlled. Furthermore we argue that noncoding regulatory RNAs, notably BACE1-AS, must be viewed as candidates for an early biomarker signature in AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short- term memory loss. Although controversy still exists in the link between amyloid pathway and AD and in the precedence of events leading to AD, deposition of A2 1-42 into senile plaques is a proven feature of AD neuropathology. BACE1 is a -site amyloid precursor protein (APP) cleaving enzyme essential for A2 1-42 biosynthesis. BACE1 is therefore a hotly pursued drug target in AD. Understanding the mechanisms by which BACE1 is regulated may reveal important insights into the pathogenesis of AD, and lead to the development of novel therapeutics and AD biomarkers.